Among the lung diseases which present with pulmonary fibrosis we have diffuse interstitial lung diseases (DILD), which constitute a group of conditions with similar clinical, radiological and functional respiratory manifestations, wherein the main anatomopathological alterations affect the alveolar-interstitial structures. Furthermore, on many occasions, they also affect the small respiratory tracts, as well as the pulmonary vessels. This group of lung diseases is characterized by the inflammation and scarring of the alveoli and their support structures (the interstice), which leads to the loss of functional alveolar units and a reduction in the transfer of oxygen from the air to the blood.
The etiology of DILDs is very varied. At present, more than 150 different causes are known, although it is only possible to identify the causal agent thereof in approximately 35% of them. Their classification has been modified recently after the consensus prepared by the American Thoracic Society (ATS) and the European Respiratory Society (ERS) (see Table 1). Several groups of DILD are distinguished. The first group corresponds to idiopathic interstitial pneumonias, although this group also includes granulomatous lung diseases, such as sarcoidosis. In the second group appear the DILD of known cause or associated to other well-defined clinical entities; said group includes the pulmonary manifestations of collagen diseases, which frequently have a histology undistinguishable from idiopathic interstitial pneumonias, as well as the DILD caused by drugs, organic dust (extrinsic allergic alveolitis), inorganic dust (pneumoconiosis) and those associated to hereditary diseases. The third group is formed by a set of diseases which, although idiopathic, have well-defined symptoms and histology.
TABLE 1Classification of diffuse interstitial lung diseases (DILD)Idiopathic interstitial pneumoniasIdiopathic pulmonaryfibrosisAcute interstitialpneumoniaNon-specific interstitial pneumoniaRespiratory bronchitis with interstitial lung disease(respiratory bronchitis/DILD)Desquamative interstitialpneumoniaCryptogenetic organizingpneumoniaLymphocytic interstitial pneumoniaSarcoidosis of known or associated causeAssociated to collagen diseasesCaused by inorganic dust (pneumoconiosis)Induced by drugs and radiotherapyCaused by organic dust (extrinsic allergic alveolitis)Associated to hereditary diseases (Hermansky-Pudlaksyndrome, etc.)Primary or associated to other not well-defined processesAlveolar proteinosisAlveolar microlithiasisLymphangioleiomyomatosisPulmonary eosinophiliasHistiocytosis X (granulomatosis of Langerhans cells)Amyloidosis
The most frequent DILDs are idiopathic pulmonary fibrosis and sarcoidosis, followed by extrinsic allergic alveolitis and those associated to collagen diseases.
Idiopathic pulmonary fibrosis (IPF) is the most frequent DILD and relates to pathologies which have a form of chronic interstitial fibrosing pneumopathy, limited to the lung and associated to a histopathological pattern of usual interstitial pneumonia (classic pattern associated to biopsy of the IPF). The estimated prevalence of the IPF is of 20 cases per each 100,000 (20/100,000) inhabitants in men and 13/100,000 in women. This disease may be presented at any age although it is most common between 40 and 70 years of age. Once the disease is diagnosed, the mortality is 50% after 5 years. The incidence, the prevalence and the mortality rate increases with age.
Its etiology is unknown and, within the iodiopathic interstitial pneumonias, it is that of worse prognosis. Most patients have the symptoms for many months (6-24 months) before being diagnosed. The first clinical manifestations include a progressive difficulty in breathing, dyspnea of effort, dry cough without apparent cause and crepitant sounds in the auscultation.
A large number of mechanisms have been proposed to explain the pathogeny of IPF. In general, it is considered that inflammatory cells act directly on the fibroblasts, through a large variety of inflammatory mediators, cytokines and growth factors, although an important role is also played by the interactions of these inflammatory modulators with the cells of the pulmonary parenchyma. As this pathological process takes place between the distal units of the lung (terminal bronchioles and alveoli), the interactions between the inflammatory cells with the epithelium and the pulmonary endothelium are also important. On the other hand, it should be highlighted that not only the inflammatory cells and the epithelials affect the fibroblasts, but they also alter the inflammatory and parenchymatic cells. In the normal lung, the interstice of the alveoli is very thin and the number of fibroblasts is limited. Most of the fibroblasts and collagen fibres are distributed throughout the vessels and the conducts of the air tracts. It seems that the balance between fibrotic and antifibrotic factors gives rise to the suppression of the proliferation of fibroblasts and the extracellular matrix.
Currently, it is considered that IPF is the end result of an unknown aggression which causes a chronic inflammation associated to the destructuring of the lung tissue and to the formation of fibrosis as a result of normal repair of the lesions. All of this would give rise to a progressive accumulation of extracellular matrix, a decrease between the fibroblast-myofibroblast balance, the continued death of epithelial cells and, finally, an abnormal re-epithelializing.
The fundamental objectives of the treatment for DILD consist, in general, of avoiding exposure to the causal agent, suppressing the inflammatory component of the disease (alveolitis) and treating the complications. The first objective can only be achieved in the diseases of known etiology. The suppression of alveolitis is the only therapeutic means in the DILDs of unknown cause, since there are no antifibrotic drugs with proven efficacy. The drugs used are glucocorticoids and immunodepressants. The indications and duration of the treatment vary according to the type of DILD. A recent study has demonstrated that sildenafil causes pulmonary vasodilation and improvement in gaseous exchange. However, there is no recommended strategy.
Although the pathogenic process suggests that there exist numerous theoretical points for different therapeutic interventions, the treatment has always been restricted, in practice, to therapies with antiflammatories and, recently, lung transplant. The different current treatments include corticosteroids (prednisone), immunosuppressants/cytotoxic agents (azathioprine, cyclofosfamide) and antifibrotic agents (colchicine or D-penicillamin) alone or in combination.
Unfortunately, none of the pharmacological therapies that have been tested have demonstrated to be useful for improving patients' prognosis.
Lung transplant is the last therapeutic option for DILDs which progress to fibrosis and cause respiratory insufficiency. There are more than 120 causes of DILD which evolve to fibrosis and, therefore, it is very difficult to identify the window of the transplant (suitable moment for the transplant in each patient, without it being too early or late that it compromises the viability of the transplant).
Currently, it is thought that the new therapies may include: oxidant agent inhibitors, cytokine inhibitors, protease inhibitors, fibroblast or growth factor inhibitors, antifibrotic drugs, modifications to the diet, better efficacy of the drugs administered via intrapulmonary route, such as the use of liposomes, antioxidants, leukocyte integrin inhibitors, and, finally, gene therapy.
Other agents with the capacity to block fibrogenesis can be used for the treatment of DILDs. Relaxin, a peptide which is used in the last phases of gestation and contributes to remodelling the pubic ligaments, decreases collagen production in fibroblast cultures and alters the balance between proteinases and anti-proteinases, in favour of the breaking of the matrix. Sumarin, a synthetic compound which has been used for many years to treat infections caused by nematodes, inhibits the effects of numerous profibrotic growth factors. Endothelin-1, a mitogenic and vasoactive peptide which is synthesized and segregates in the vascular endothelium and in the epithelium of the air tracts, has been found associated to the fibroblastic focus of biopsies and it can be obtained in the broncho-alveolar washes; in animal models, the inhibition of endothelin-1 avoids scarring after causing a pulmonary lesion. Angiotensin II is another peptide with mitogenic effects in the fibroblasts.
Since the epithelial lesion can also be produced, in part, by oxygen free radicals (OFR), it has been suggested that antioxidant strategies can be beneficial. Possible strategies will include the administration of antioxidant enzymes or promoting an increase in the gene expression thereof. The natural scavenger agent of the OFR suppresses the proliferation of pulmonary fibroblasts in response to mitogens. Taurine and niacin inhibit the development of fibrosis in animal models: the use of high doses of N-acetyl-L-cysteine, as glutation precursor, taurine and OFR scavenger agents, as therapeutic combination in immunosuppressant therapies for the FPL.
Another potential strategy for the treatment of said DILDs could be interference in the process of leukocyte recruitments. The adhesion molecules play a very important role in this process. Antibodies against these adhesion molecules have shown prevention in the deposition of collagens in animal models of pulmonary lesion.
Immunomodulating drugs have also been studied in both in vitro studies and in research animals. These works suggest that the modification of the inflammatory response in tissue repair may modulate the degree of final fibrosis after pulmonary lesion.
An effective therapy should try to prevent or inhibit the fibroproliferative response and be aimed at improving the repair of alveolar re-epitheliazing. In this way, the impact of the disease would be reduced, improving the patients' health. In other words, it would be suitable to induce the death of the fibroblasts, and not those of the epithelial cells, since this would give rise to good re-epitheliazing. However, some studies suggest that the inhibition of the fibroblast growth does not give rise to good re-epitheliazing [Bowden D H, Young L, Adamson I Y. Fibroblast inhibition does not promote normal lung repair after hyperoxia. Exp Lung Res 1994; 20:251-262].
Another therapeutic challenge is related to the possibility that the agents capable of directly inducing the proliferation of the type II epithelial cells decrease the fibrotic response to different aggressions and reduce cell death.